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RS1-00205-1: Generation of forebrain neurons from human embryonic stem cells

Recommendation: Recommended if funds available
Scientific Score: 96

First Year Funds Requested: $304,035.00
Total Funds Requested: $612,075.00

Public Abstract (provided by applicant)

The goal of this proposal is to generate forebrain neurons from human embryonic stem cells. Our general strategy is to sequentially expose ES cells to signals that lead to differentiation along a neuronal lineage, and to select for cells that display characteristics of forebrain neurons. These cells would then be used in transplantation experiments to determine if they are able to make synaptic connections with host neurons. If successful these experiments would provide a therapeutic strategy for the treatment of Alzheimer’s disease and other disorders that are characterized by loss of forebrain neurons. Currently there is no effective treatments for Alzheimer’s disease, and with an aging baby-boomer population, the incidence of this disease is likely to increase sharply. One of the few promising avenues to treat Alzheimer’s is the possibility of cell replacement therapy in which the neurons lost could be replaced by transplanted neurons. Embryonic stem cells, which have the ability to differentiate into various cells of the body, could be a key component of such a therapy if we can successfully differentiate them into forebrain neurons.

Statement of Benefit to California (provided by applicant)

Alzheimer’s disease is a devastating sporadic neurological disorder that places all of us at risk. As the California population ages, there will be a significant increase in the incidence of Alzheimer’s disease, and the medical and financial cost on the state will be severe. There are currently no effective treatments for this disorder, and one of the few promises is the possibility of transplantation therapy to replace the neurons that are lost in the disease. Being able to generate forebrain neurons from human embryonic stem cells would provide a key tool in the fight against this disease. Needless to say, the development of an effective cell replacement therapy would not only be of immense medical significance as we care for our senior population, it will also greatly relieve the financial burden associated with the care of Alzheimer’s patients, which is often borne by the state.

Review

SYNOPSIS OF PROPOSAL: This proposal describes fundamental work on forebrain neuron specification of hESC.

INNOVATION AND SIGNIFICANCE: This proposal is solid, important, and based on strong and clear biology.

This is an extremely innovative and important proposal from one of the world’s best developmental neurobiologists who will study controlled differentiation of different forebrain neuronal populations from hESC. The ability to generate desired populations of cortical neuronal progenitors for future therapies based on protecting or replacing these cells in neurological disease would be a huge leap forward in restorative neurology and neuroscience. This gifted and productive investigator is the best person in the world for this job.

This work will motivate and advance the field.

STRENGTHS OF PROPOSAL:This is an incredibly strong and important proposal to generate neuronal populations from hESC that exhibit forebrain phenotypes and characterize their nature, synaptogenic potential, and functional integration within cortical and hippocampal circuitries. There is no one better in the world to do this work than the PI.

It is ingenious to systematically and temporally introduce different specific genes into hESC to direct them toward divergent lineages. The selected molecules are perfect starting points, and the experiments are sure to reveal important new findings on the generation of designer cells from embryonic stem cells for future therapeutic applications.

The isolation and differentiation protocols are all well-designed and the rigor is appropriate.

The collaborative team of solid stem cell and developmental neurobiologists is well-suited to do these studies.

WEAKNESSES OF PROPOSAL: There are few weaknesses, and they are mostly at the detail level.

DISCUSSION: This was the top-ranked application (of those they read) by both reviewers. The applicant is a world-quality developmental biologist who wants to study forebrain neuron development from hESC.

There was a question as to whether evidence exists to support the idea that the desired neurons can be expanded given previously observation come from studies in mouse; is there comfort that this will work in the human system? A reviewer responded the study is to use early progenitors and then put them into the mouse. At least 4 of the many factors proposed for study have direct human homologs. It was also noted that specific forebrain genes have homologs as well. All agreed however that the effects are likely to be combinatorial.

There is quite a bit of transgenic work to be done. The project may not work but the applicant is the right researcher to try it.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• None